It has become clear that an internal death program controls the number and types of cells in the body. Diseases can result from inefficient cell death or from inappropriate or excessive death such as is caused by the human immunodeficiency virus (HIV) during AIDS. In this project we are taking a multifaceted approach to studying molecular mechanisms of this death program in lymphocytes as well as other cell types. A major focus of our investigations is a cell surface receptor called CD95/Fas/APO-1 that plays an important role in stimulating the death of cells mainly in the immune system. We are trying to understand how this receptor stimulates the intracellular machinery that causes cellular demise. In particular we have focused on the activation of a protease termed Flice/Mach1 (caspase-8) which can directly carry out the death program. We have characterized two death programs that emanate from the Fas receptor, one which is caspase-8 dependent and the other which is caspase-8 independent. The regulation and molecular pathways of these two forms of lymphocyte death are distinct. In addition, we have discovered a major program of cell death exhibiting particular cytoplasmic membrane structures called autophagy which is triggered by the inhibition of caspase-8. These studies will help us to determine how cells can initiate their own death. We are exploring how the regulation of this event may play a role in various diseases ranging from autoimmune conditions to infectious diseases such as AIDS, SARS, and mycobacterial infections. In particular, following infection with HIV, a critical effect in the onset of AIDS is believed to be death of T lymphocytes caused by the virus. We have found that this death process is distinct from apoptosis and are making progress in indentifying the viral gene product(s)that are involved in this process. We would then like to explain how the virus product triggers the death of T cells in biochemical terms.